The synthesis of compounds that possess unique chemical structures, shapes, and physical properties is an important objective of diversity-oriented synthesis (DOS). The identification of compounds that perturb biological processes from high-throughput screening efforts greatly enhance the ability to perform fundamental biomedical research. A distinct approach to obtain molecules with novel chemical properties is the construction of small molecule libraries from scaffold structures. This proposal outlines specific plans for a Pilot Scale Libraries (PSL) initiative to synthesize a selection of structurally complex heterocyclic compounds for inclusion into the National Institutes of Health Molecular Library Small Molecule Repository (MLSMR). The library Projects outlined in the proposal illustrate the Principal Investigator's (PI's) and Co-Principal Investigator's (Co-PI's) interest in the design and synthesis of complex molecules possessing unique shapes, stereochemical arrangements, and chemical properties. A total of 14 libraries are described with distinct structures. The library designs have been compared against the National Center for Biotechnology Information molecular database PubChem to ensure that each compound is unique and accesses novel chemical space properties. Furthermore, library design criteria has also included calculated physiochemical properties and solubility properties that are consistent with bioactive natural product-like characteristics. Target libraries include pyrimidones and related compounds, natural product-inspired compounds, polyketide-derived heterocycles, and carbazole-derived libraries. A key mechanism for data sharing for the PSL initiative includes uploading the compound library structures to the PubChem database and linking the compound IDs to an Internet-based Synthesis Protocol Database that is publicly accessible and capable of providing detailed synthetic procedures for the compounds synthesized as a part of the PSL initiative. The compound libraries developed in this effort are anticipated to facilitate the discovery of new chemical probes of biological and cellular processes through the Molecular Libraries Initiative. PUBLIC HEALTH RELEVANCE: The compounds synthesized during this project will be used to support the National institutes of Health Molecular Libraries initiative and National Small Molecule Repository Resource. The proposed projects will create valuable research tools to study biology and support the biomedical research community created by the NIH.